ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma))

Note	The ADAM9 gene transcript 2 isoforms of mRNA with altered splicing results the lost of exon 18 in the second isoform of ADAM9 mRNA and early stop codon.
	ADAM9 gene is located on chromosome 8p11.23 spread out on 108,276 deoxynucleotides contained 22 exons. The coding sequence of ADAM9 is 2460 nucleotides. Two isoforms reported, isoform 1 of ADAM9 carried full-length membrane bond ADAM9 and isoform 2 carried soluble form of ADAM9 (sADAM9). The sADAM9 is due to alternative splicing in which lost of exon 18 and results in early stop translation in exon 19.
Description	ADAM9 gene extends 108,276 base pairs with 22 exons which gives rise to 2 different ADAM9 transcripts with differential splicing. The mRNA of ADAM9 isoform 1 is 4111 base pair and isoform 2 is 4005. ADAM9 isoform 2 lacks exon 18 of isoform 1 in the coding region, which results in a frameshift and an early stop codon. The isoform 2 lacks the c-terminal transmembrane and cytoplasmic domains and is a secreted form.
Transcription	Isoform 1 mRNA of ADAM9 (NM_003816) has a size of 4111 bp, isoform 2 mRNA (NM_001005845) has a size of 4005 bp. ADAM9 mRNA is equally expressed in many tissue. Among cancer progression, ADAM9 mRNA is relatively highly expressed in prostate cancer and breast cancer. However, little is known of differential expression between different isoform of ADAM9.
Pseudogene	No pseudogene has reported for ADAM9.

Note	Two different isoform of ADAM9 was reported, the full length and soluble form of ADAM9. Recent report suggests promoter polymorphisms regulated ADAM9 transcription that play a protective role against Alzheimer's disease.
	Two isoforms of ADAM9 with their specific function. Soluble form of ADAM9 has function to active APP either on the same cell or neighbor cell.
Description	The predicted molecular mass of ADAM9 is about 84 KDa. ADAM9 contained coding sequence of 2460 nucleotides which encoding amino acid of 819 residues. The full length of active ADAM9 contained several functional regions including metalloproteinase, disintegrin, cystein rich, EGF-like, transmembrane and cytoplasmic domains. The pro-domain of ADAM9 was removed by furin-type convertase during ADAM9 translocated onto membrane and become active form. Recent reports indicated soluble form of ADAM9 cloned from human cDNA library that showed increased of cancer invasion in malignant progression.
Expression	ADAM9 is ubiquitously expressed. SAGE analyses of ADAM9 expression demonstrated that ADAM9 is expressed in the bone marrow, lymph node, brain, retina, heart, skin, muscle, lung, prostate, breast and placenta. Increased expression of ADAM9 was reported in several cancers, including gastric, breast, prostate, colon, and pancreatic cancers. Splicing alteration and lost of exon 18 of ADAM9 causes lost of transmembrane domain and early stop in soluble form of ADAM9.
Localisation	Full length has N-terminal signal peptide and a single hydrophobic region predicted to be transmembrane domain. Hence, the full length of ADAM9 is localized to the plasma membrane. Soluble ADAM9 lack the transmembrane domain and cytoplasmic domain and to be released out of cell.
Function	1. Ectodomain shedding: Metalloproteinase domain of ADAM9 is zinc dependent. Metalloproteinase has been showed to involve ectodomain shedding (see table below). One such protein is the heparin-binding EGF-like growth factor (HB-EGF) and amyloid precursor protein (APP). TABLE : Substrate and Peptide Sequence Cleaved Substrate Peptide sequence cleaved (*: cleave site) Amyloid precursor protein EVHH*QKLVFFAE TNF-a SPLA*QAVRS*SSR P75 TNF receptor SMAPGAVH*LPQP c-kit ligand LPPVA*A*S*SLRND Insulin B Chain LVEALY*LVCGERGFFY*TPKA HB-EGF GLSLPVE*NRLYTYD 2. Matrix Degradation: purified metalloproteinase domain of ADAM9 showed the ability to digest fibronectin, gelatin and beta-casein. Secreted form of ADAM9 showed the ability to digest laminin and promote cancer invasion. 3. Cell contact: ADAM9 specifically bind to integrin alpha6beta1, a laminin receptor, via disintegrin region of ADAM9 through non-RGD mechanism. ADAM9 also have been implicated in binding of avbeta5 in divalent cation dependent condition, suggests ADAM9 can function as adhesion molecule for cell-cell and cell-martrix interaction. Secreted form of ADAM9 binds directly to alpha6beta4 and alpha2beta1 integrin and ability to cleave laminin and promote cancer progression. 4. Cysteine-Rich domain: The ADAM Cysteine-rich domain is not found in other organisms, such as virus, archaeal, bacterial or plant. The function of cysteine-rich domain might involved in complement the binding ability of disintegrin-mediated interactions.
Homology	The table below gives homology between the human ADAM9 and others organisms.

Note	Single nucleotide polymorphosim analyses of chromosome 8 demonstrated about 356 SNP in the chromosome 8p11.23. Most of them are located in intron of ADAM9. No mutation was reported in ADAM9 coding sequence. Recent evidence suggests promoter polymorphisms that may upregulate ADAM9 transcription, such as -1314C has higher of transcription activities.
	ADAM9 gene promoter region contained 4 polymorphisms: -542C/T, -600A/C, -963A/G and -1314T/C. 1314C showed higher ADAM9 transcription compared to 1314T.

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